A novel 3D computational model of a cardiac calcium release unit demonstrates that dye kinetics and optical averaging explain the discrepancy between predicted and measured local calcium depletion during sparks.
Does not alter clinical care; extends animal Ca2+ spark models but requires validation before broader inference.
We have developed a detailed computational model of a cardiac Ca2+ spark based on a three dimensional reconstruction of electron tomograms. Our model predicts near total junctional Ca2+ depletion after the spark, while regional Ca2+ reserve is preserved. The local Ca2+ gradient inferred by these findings reconciles previous model predictions with experimental measurements. Differences in local distribution of calsequestrin have a profound impact on spark termination time, as reported by Fluo5, solely based on its Ca2+ buffering capacity. The SERCA pump can prolong spark release time by pumping Ca2+ back into the junctional SR during the spark. Abstract Triggered release of Ca2+ from an individual sarcoplasmic reticulum (SR) Ca2+ release unit (CRU) is the fundamental event of cardiac excitation–contraction coupling, and spontaneous release events (sparks) are the major contributor to diastolic Ca2+ leak in cardiomyocytes. Previous model studies have predicted that the duration and magnitude of the spark is determined by the local CRU geometry, as well as the localization and density of Ca2+ handling proteins. We have created a detailed computational model of a CRU, and developed novel tools to generate the computational geometry from electron tomographic images. Ca2+ diffusion was modelled within the SR and the cytosol to examine the effects of localization and density of the Na+/Ca2+ exchanger, sarco/endoplasmic reticulum Ca2+-ATPase 2 (SERCA), and calsequestrin on spark dynamics. We reconcile previous model predictions of approximately 90% local Ca2+ depletion in junctional SR, with experimental reports of about 40%. This analysis supports the hypothesis that dye kinetics and optical averaging effects can have a significant impact on measures of spark dynamics. Our model also predicts that distributing calsequestrin within non-junctional Z-disc SR compartments, in addition to the junctional compartment, prolongs spark release time as reported by Fluo5. By pumping Ca2+ back into the SR during a release, SERCA is able to prolong a Ca2+ spark, and this may contribute to SERCA-dependent changes in Ca2+ wave speed. Finally, we show that including the Na+/Ca2+ exchanger inside the dyadic cleft does not alter local [Ca2+] during a spark.
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Hake et al. (2012) studied this question.
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